Taniuchi Ichiro, Osato Motomi, Egawa Takeshi, Sunshine Mary Jean, Bae Suk Chul, Komori Toshihisa, Ito Yoshiaki, Littman Dan R
Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Cell. 2002 Nov 27;111(5):621-33. doi: 10.1016/s0092-8674(02)01111-x.
T lymphocytes differentiate in discrete stages within the thymus. Immature thymocytes lacking CD4 and CD8 coreceptors differentiate into double-positive cells (CD4(+)CD8(+)), which are selected to become either CD4(+)CD8(-)helper cells or CD4(-)CD8(+) cytotoxic cells. A stage-specific transcriptional silencer regulates expression of CD4 in both immature and CD4(-)CD8(+) thymocytes. We show here that binding sites for Runt domain transcription factors are essential for CD4 silencer function at both stages, and that different Runx family members are required to fulfill unique functions at each stage. Runx1 is required for active repression in CD4(-)CD8(-) thymocytes whereas Runx3 is required for establishing epigenetic silencing in cytotoxic lineage thymocytes. Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes.
T淋巴细胞在胸腺内经历离散阶段分化。缺乏CD4和CD8共受体的未成熟胸腺细胞分化为双阳性细胞（CD4(+)CD8(+)），这些细胞随后被选择成为CD4(+)CD8(-)辅助细胞或CD4(-)CD8(+)细胞毒性细胞。一种阶段特异性转录沉默子调节未成熟和CD4(-)CD8(+)胸腺细胞中CD4的表达。我们在此表明，Runt结构域转录因子的结合位点对于两个阶段的CD4沉默子功能至关重要，并且不同的Runx家族成员在每个阶段需要履行独特功能。Runx1是CD4(-)CD8(-)胸腺细胞中活性抑制所必需的，而Runx3是细胞毒性谱系胸腺细胞中建立表观遗传沉默所必需的。Runx3缺陷的细胞毒性T细胞而非辅助细胞对抗原有缺陷反应, 这表明Runx蛋白在CD8谱系T淋巴细胞的谱系特化和稳态中具有关键功能。
